Antiestrogenic and antitumor properties of tamoxifen in laboratory animals.

This paper reviews the antiestrogenic and antitumor properties of tamoxifen (NSC-180973; ICI-46474) in the rat. In classic tests for antiestrogenic activity, tamoxifen inhibits the actions of estradiol in the rat uterus and vagina. At the cellular level, tamoxifen inhibits estrogen binding to cytoplasmic estrogen receptors, but although estrogen-receptor units are translocated to the nucleus DNA synthesis does not occur. It is suggested that tamoxifen competes for estrogen receptors in the cytoplasm and the false messenger units block the nuclear acceptors which are normally activated by estradiol-estrogen receptor complexes thereby provoking DNA synthesis. Tamoxifen inhibits the growth of some 7.12-dimethylbenz(a)anthracene-induced rat mammary tumors whereas others continue to grow. Estrogen-stimulated rises in plasma prolactin are only partially inhibited by tamoxifen although at the tumor level, tamoxifen completely blocks estrogen binding. There is a linear correlation (P less than 0.01) between estrogen-receptor levels in tumor biopsies before therapy and tumor responses to 3 weeks of tamoxifen treatment (50 mug/day) i.e., tumors with low levels of estrogen receptors do not respond to therapy whereas tumors with higher levels of estrogen receptors regress. It is suggested that tamoxifen antagonizes the actions of estrogen at the tumor level by blocking the estrogen-receptor mechanism thereby producing tumor regression. Therefore, estrogen-receptor measurements in tumor biopsies before therapy may be a useful predictive test for the tumor response to tamoxifen treatment.